Excellent Renal Allograft Survival in Donor-Specific Antibody Transplant Patients—Role of Intravenous Immunoglobulin and Rabbit Antithymocyte Globulin

Dhanda, Raman; Shah, Yasser; Bardapure, Mallikarjun; Bhattacharjya, Shantanu; Sharma, Ajay

doi:10.1097/tp.0b013e3181af3914

Cited by 4 publications

(3 citation statements)

References 4 publications

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“…IVIg has been used for > 3 decades in allosensitized patients undergoing organ transplantation, and also in the treatment of autoimmune diseases, such as Kawasaki disease, idiopathic thrombocytopenic purpura, and myasthenia gravis 13 . In allotransplantation, there is some evidence of the efficacy of IVIg as an immunomodulatory agent in highly HLA-sensitized patients [43][44][45] and in the treatment of antibody-mediated rejection 46 . The effect of IVIg in xenotransplantation remains controversial, with some groups reporting a benefit 16,31,39,40 , but others reporting no benefit 18 or even harm 5 .…”

Section: A B Discussionmentioning

confidence: 99%

Effect of intravenous immunoglobulin (IVIg) on primate complement-dependent cytotoxicity of genetically engineered pig cells: relevance to clinical xenotransplantation

Yamamoto

Cui

Patel

et al. 2020

Sci Rep

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Triple-knockout (TKO) pigs may be ideal sources of organs for clinical xenotransplantation because many humans have no preformed antibody to TKO pig cells. Intravenous immunoglobulin (IVIg) is widely used for severe infection or the treatment/prevention of antibody-mediated rejection in allotransplantation. Anti-pig antibodies in IVIg could be harmful in clinical xenotransplantation. It is unknown whether anti-TKO pig antibodies are present in IVIg. The main aim of this study was to investigate in vitro whether IVIg contains anti-TKO pig antibodies with cytotoxic effect to pig cells. Undiluted pooled human serum (HS) and five different commercial preparations of IVIg were tested for IgM and IgG binding to red blood cells (RBCs) from wild-type (WT), α1,3-galactosyltransferase gene-knockout (GTKO), and TKO pigs by flow cytometry. Complement-dependent lysis of IVIg against these pig pRBCs was measured by hemolytic assay. Pooled HS and 4 of 5 IVIg commercial preparations contained anti-pig IgG that bound to WT and GTKO pRBCs, but not to TKO pRBCs. One preparation of IVIg contained antibodies that bound to TKO pRBCs, but there was no cytotoxicity of IVIg to TKO pRBCs. The results suggest that IVIg administration to human recipients of TKO pig grafts would be safe. However, the specific preparation of IVIg would need to be screened before its administration. Abbreviations Gal Galactose-α1,3-galactose GTKO α1,3-Galactosyltransfearse gene-knockout IVIg Intravenous immunoglobulin Neu5Gc N-Glycolylneuraminic acid NHP Nonhuman primate pAECs Pig aortic endothelial cells pRBCs Pig red blood cells TKO Triple gene-knockout WT Wild-type Genetically-modified pigs could be an alternative source of organs for clinical transplantation.

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Section: A B Discussionmentioning

confidence: 99%

Effect of intravenous immunoglobulin (IVIg) on primate complement-dependent cytotoxicity of genetically engineered pig cells: relevance to clinical xenotransplantation

Yamamoto

Cui

Patel

et al. 2020

Sci Rep

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“…10 Our group previously identified 10 different brands of commercially available IVIg in the United States. 11 IVIg has been used for >3 decades in the prevention or treatment of antibody-mediated rejection in HLA-sensitized patients undergoing organ allotransplantation and in those receiving ABO-incompatible kidney allografts, 10,[12][13][14][15][16][17][18][19] usually as an adjuvant intended to suppress rebound of alloantibody. IVIg is also used in the treatment of autoimmune diseases, such as Kawasaki disease, idiopathic thrombocytopenic purpura, and myasthenia gravis 20,21 and treatment of severe infection.…”

Section: Intravenous Immunoglobulin (Ivig) Therapymentioning

confidence: 99%

The first clinical pig heart transplant: Was IVIg or pig cytomegalovirus detrimental to the outcome?

Cooper

Yamamoto

Hara

et al. 2022

Xenotransplantation

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The clinical course of the first patient to receive a gene-edited pig heart transplant was recently reported by the University of Maryland team. Although the pig heart functioned well for >40 days, serum anti-pig antibodies then increased, and the patient sadly died after 60 days. Because of his debilitated pre-transplant state, the patient never thrived despite excellent graft function for several weeks, and the cause of his demise continues to be uncertain. A few days before an increase in anti-pig antibodies was observed, the patient had received intravenous human immunoglobulin (IVIg), and whether this played a role in his cardiac deterioration has been discussed. Furthermore, mcfDNA testing indicated an increase in pig cytomegalovirus (CMV), and its possible role in the development of cardiac dysfunction has also been considered.On the basis of the limited data provided in the publication and on our previous investigations into whether IVIg contains anti-TKO pig antibodies and therefore might be deleterious to TKO pig organ xenografts, we suggest that the steady rise in anti-pig antibody titer was more consistent with the failure of the immunosuppressive regimen to prevent elicited anti-TKO pig antibody production, rather than from the passive transfusion of IVIg or the presence of pig CMV in the graft. Although the outcome of the Maryland experience was disappointing, valuable lessons were learned. Our attention was drawn to the potential risks of heart transplantation in a "deconditioned" patient, the administration of IVIg, the transmission of pig CMV, and of the difficulties in interpreting myocardial biopsy findings.

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“…Alloreactive Tms can be developed by transplantation recipients if they were exposed to the alloantigen during previous transplantations, blood transfusions, and pregnancies, or as a result of the continuous exposure to viral pathogens and bacteria. These memory cells play a pivotal role in poor allograft outcomes [2][3][4]. Compared with naïve cells, Tms have lower activation thresholds, precommitted cytokine profiles, and fewer dependent costimulations [5,6], which make them significant obstacle to prolonging allograft survival after initial and secondary transplants.…”

Section: Introductionmentioning

confidence: 99%

Thalidomide with blockade of co-stimulatory molecules prolongs the survival of alloantigen-primed mice with cardiac allografts

Zhu

Tan

et al. 2020

BMC Immunol

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Background: Miscellaneous memory cell populations that exist before organ transplantation are crucial barriers to transplantation. In the present study, we used a skin-primed heart transplantation model in mouse to evaluate the abilities of Thalidomide (TD), alone or in combination with co-stimulatory blockade, using monoclonal antibodies (mAbs) against memory T cells and alloantibodies to prolong the second cardiac survival. Results: In the skin-primed heart transplantation model, TD combined with mAbs significantly prolonged the second cardiac survival, accompanied by inhibition of memory CD8 + T cells. This combined treatment enhanced the CD4 + Foxp3 + regulatory T cells ratio in the spleen, restrained the infiltration of lymphocytes into the allograft, and suppressed the allo-response of spleen T cells in the recipient. The levels of allo-antibodies also decreased in the recipient serum. In addition, we detected low levels of the constitutions of the lytic machinery of cytotoxic cells, which cause allograft damage. Conclusions: Our study indicated a potential synergistic action of TD in combination with with mAbs to suppress the function of memory T cells and increase the survival of second allografts in alloantigen-primed mice.

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Excellent Renal Allograft Survival in Donor-Specific Antibody Transplant Patients—Role of Intravenous Immunoglobulin and Rabbit Antithymocyte Globulin

Cited by 4 publications

References 4 publications

Effect of intravenous immunoglobulin (IVIg) on primate complement-dependent cytotoxicity of genetically engineered pig cells: relevance to clinical xenotransplantation

Effect of intravenous immunoglobulin (IVIg) on primate complement-dependent cytotoxicity of genetically engineered pig cells: relevance to clinical xenotransplantation

The first clinical pig heart transplant: Was IVIg or pig cytomegalovirus detrimental to the outcome?

Thalidomide with blockade of co-stimulatory molecules prolongs the survival of alloantigen-primed mice with cardiac allografts

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